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We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear.A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations.One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005).Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene–HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0–1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

Nemonoxacin, a novel nonfluorinated quinolone, exhibits potent in vitro and in vivo activities against community-acquired pneumonia (CAP) pathogens, including multidrug-resistant Streptococcus pneumoniae . Patients with mild to moderate CAP ( n = 265) were randomized to receive oral nemonoxacin (750 mg or 500 mg) or levofloxacin (500 mg) once daily for 7 days. Clinical responses were determined at the test-of-cure visit in intent-to-treat (ITT), clinical per protocol (PPc), evaluable-ITT, and evaluable-PPc populations. The clinical cure rates for 750 mg nemonoxacin, 500 mg nemonoxacin, and levofloxacin were 89.9%, 87.0%, and 91.1%, respectively, in the evaluable-ITT population; 91.7%, 87.7%, and 90.3%, respectively, in the evaluable-PPc population; 82.6%, 75.3%, and 80.0%, respectively, in the ITT population; and 83.5%, 78.0%, and 82.3%, respectively, in the PPc population. Noninferiority to levofloxacin was demonstrated in both the 750-mg and 500-mg nemonoxacin groups for the evaluable-ITT and evaluable-PPc populations, and also in the 750 mg nemonoxacin group for the ITT and PPc populations. Overall bacteriological success rates were high for all treatment groups in the evaluable-bacteriological ITT population (90.2% in the 750 mg nemonoxacin group, 84.8% in the 500 mg nemonoxacin group, and 92.0% in the levofloxacin group). All three treatments were well tolerated, and no drug-related serious adverse events were observed. Overall, oral nemonoxacin (both 750 mg and 500 mg) administered for 7 days resulted in high clinical and bacteriological success rates in CAP patients. Further, good tolerability and excellent activity against common causative pathogens were demonstrated. Nemonoxacin (750 mg and 500 mg) once daily is as effective and safe as levofloxacin (500 mg) once daily for the treatment of CAP.

Introduction:Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that significantly increases survival for patients with previously treated advanced non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be particularly effective in Asian patients and may have a distinct safety profile in this population compared with non-Asian patients. We report safety and efficacy data from a subpopulation of East/South-East (E/SE) Asian patients enrolled in a global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment study).Methods:Patients who had previously failed on chemotherapy or radiotherapy, or were unsuitable for these treatments, were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity.Results:Best response data were available for 1118 E/SE Asian and 4276 non-E/SE Asian patients. The overall response rates were 27% versus 10%, respectively (p < 0.0001). The disease control rates were 78% versus 66%, respectively (p < 0.0001). Survival data were available for 1242 E/SE Asian and 5338 non-E/SE Asian patients. The median progression-free survival times were 5.78 months versus 2.92 months, respectively (hazard ratio = 0.66, p < 0.0001). The median overall survival times were 14.7 months versus 6.8 months, respectively (hazard ratio = 0.57, p < 0.0001). One-year survival rates were 58.3% and 32.7%, respectively. Safety data were available for 1242 E/SE Asian patients. Seventeen percent of these patients experienced one or more erlotinib-related adverse event (AE) (other than the most frequently occurring AEs prespecified in the protocol) and 2% experienced an erlotinib-related serious AE. Dose reductions were reported for 171 (14%) patients.Conclusion:Erlotinib is an effective and well-tolerated treatment for Asian patients with advanced non-small cell lung cancer.

Acute respiratory distress syndrome (ARDS), a serious inflammatory reaction to acute lung injury, is associated with high mortality rates. Decoy receptor (DcR) 3 is a soluble protein with immunomodulatory effects. Biomarkers that reliably predict outcomes in ARDS are not currently available.Comparing DcR3 with the Acute Physiology and Chronic Health Evaluation (APACHE) II scores and three other plasma markers to explore the association of DcR3 and the clinical outcome in ARDS.Eighty-eight patients with ARDS were studied. Baseline APACHE II scores and clinical data were recorded. Plasma levels of DcR3, soluble triggering receptor expressed on myeloid cells (sTREM)-1, tumor necrosis factor (TNF)-alpha, and IL-6 were measured on Day 1 and later time points, and correlated with the survival status on Day 28 after the onset of ARDS. For validation, 59 patients with ARDS from another medical center were studied.Among the biomarkers evaluated, only DcR3 discriminated the survivors and nonsurvivors at all time points in the first week of ARDS. DcR3 independently associated with and best predicted the 28-day mortality of patients with ARDS. Plasma DcR3 levels most correlated to multiple-organ dysfunction and ventilator dependence. Compared with survivors, the nonsurvivors had higher DcR3 levels regardless of the APACHE II scores. Kaplan-Meier survival analysis showed higher mortality in patients with ARDS with higher DcR3 levels. The outcome prediction of patients with ARDS by plasma DcR3 levels was recapitulated by the validation cohort.High plasma DcR3 levels correlate with development of multiple-organ dysfunction and independently predict the 28-day mortality in patients with ARDS.

Background: Severe acute respiratory syndrome (SARS) is an emerging infectious disease, and indeed, the SARS epidemic in Taiwan from March to July 2003 had a great impact. This study depicts the clinical characteristics and short-term outcomes of patients with SARS treated at Taipei Veterans General Hospital; potential predictive factors for acute respiratory distress syndrome (ARDS) are also analyzed. Methods: This study retrospectively analyzed data for 67 SARS patients, who were grouped according to whether or not ARDS developed during the clinical course of SARS. Results: There were 32 males (mean age, 50.3 years; range, 20‐75 years) and 35 females (mean age, 51.1 years; range, 23‐86 years). Twenty-five patients (37.3%) were health care workers. At admission, 50 patients (74.6%) had abnormal chest radiographs, and all patients developed pulmonary infiltrates during the following week. During hospitalization, lymphopenia was found in 57 patients (85.1%); and elevated levels of lactate dehydrogenase (LDH; n = 55; 83.3%), C-reactive protein (n = 55; 83.3%), aminotransferases (n = 44; 65.7%), and creatine kinase (n = 14; 20.9%) were also noted. ARDS developed in 33 patients (49.3%), who were generally older than the patients in whom ARDS did not develop, male, non-health care workers, and who generally had dyspnea at the time of diagnosis, and a history of diabetes mellitus, hypertension or cerebrovascular accident. Patients with, versus those without, ARDS also tended to present with more severe lymphopenia and leukocytosis, and with higher levels of LDH and aspartate aminotransferase. The overall mortality rate was 31.3% (21/67), whereas the rate for patients who developed ARDS was 63.6% (21/33). Multivariate analyses showed that age greater than 65 years (odds ratio, OR, 10.6; 95% confidence interval, CI, 2.1‐54.1), pre-existing diabetes mellitus (OR, 13.7; 95% CI, 1.3‐146.9), and elevated levels of LDH (OR, 8.4; 95% CI, 1.9‐36.9) at admission, were independent predictors of ARDS. Conclusion: The clinical manifestations of SARS showed high variability, and were related to the underlying health status of individual patients. Importantly, the development of ARDS was associated with significant mortality, despite aggressive therapy. [J Chin Med Assoc 2005;68(1):4‐10]

Purpose The aim of the study was to identify characteristic clinical features and outcomes of critically ill patients with confirmed severe acute respiratory syndrome (SARS). Materials and Methods This retrospective study enrolled all patients admitted to a 12-bed SARS intensive care unit (ICU) in a tertiary care medical center in Taipei between May 15 and July 17, 2003. Patients with positive results of either reverse transcriptase–polymerase chain reaction or antibody to SARS coronavirus were defined as SARS cases and others with negative results as control cases. Results Of the 50 patients, 14 had confirmed SARS. Demographics were similar between the 2 groups. The highest leukocyte and neutrophil counts, lactate dehydrogenase, and creatine kinase; positive end-expiratory pressure; and use of corticosteroids, ribavirin, and intravenous immunoglobulin were higher in the SARS group. In contrast, the lowest lymphocyte count and the ratio of Pa o 2 to the fraction of inspired oxygen were lower in the SARS group. Of the 15 deaths in the control group, 12 (80%) occurred during the first 2 weeks after ICU admission. However, in the confirmed SARS group, 5 (55.6%) of the 9 deaths occurred within the third or fourth week. This difference in timing between these 2 groups was significant ( P = .004). Conclusions In a SARS ICU, patients with a confirmed diagnosis of SARS had significantly different clinical features and timing of mortality from those of the control group.

Summary Purpose Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which has demonstrated a survival benefit in non-small-cell lung cancer (NSCLC) patients. An open label phase II study was conducted in Taiwanese patients with NSCLC to evaluate its efficacy. Methods Patients with proven stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy were enrolled into this study. All patients were given oral erlotinib, 150 mg/day till disease progression. Results From May 2005 to July 2006, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of erlotinib. The best response rates were a 29% partial response and 44% stable disease in 273 patients who had response data available. Non-smoking (p = 0.033), adenocarcinoma/BAC (p = 0.0027), female (p = 0.0013), aged less than 65 years (p = 0.0115), stage IV (p = 0.0492), patients with skin rash (p = 0.0216), and a higher grade of skin rash (p = 0.003) were significantly correlated with response to treatment. Skin rash was a common adverse event (any grade: 84%, Gr 3–4: 16%). The median time to disease progression was 5.6 months. Cox regression model for progression free survival showed patients most at risk of early progression were males of low performance status having squamous cell carcinoma. Conclusions This was the largest multicenter prospective clinical study of NSCLC in Taiwan. The results demonstrated the excellent response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese NSCLC patients who had been previously treated with chemotherapy or radiotherapy.

Summary Purpose Our aim here was to determine whether or not the addition of cisplatin into vinorelbine (V) treatment is an appropriate regimen for physically fit chemo-naive non-small cell lung cancer (NSCLC) patients aged 70 or older. Patients and methods Patients were randomized into vinorelbine (V) or vinorelbine plus cisplatin (VP) treatment arms. Treatment consisted of vinorelbine 25 mg/m 2 intravenous infusion (IV) on days 1 and 8 every 3 weeks (V arm), or vinorelbine 22.5 mg/m 2 IV on days 1 and 8 plus cisplatin 50 mg/m 2 IV on day 1 every 3 weeks (VP arm). Results Sixty-five patients were enrolled from May 2005 to December 2006, including 31 who received V treatment and 34 who received VP treatment. Objective response rates were 16.1% in V and 32.4% in VP ( p = 0.009). Control rates were 51.6% in V and 82.4% in VP ( p = 0.008). Myelosuppression was more common and severe in the VP arm. Any grade of anemia and neutropenia was significantly higher in the VP arm ( p = 0.001 and 0.009, respectively). Fatigue sensation was more common and severe in the VP arm ( p = 0.032). Median time to disease progression was 3.1 months in the V arm and 5.2 months in the VP arm ( p = 0.0303). The 1-year survival rate was 50.9% in the V arm and 47.2% in the VP arm. Conclusions Adding cisplatin to vinorelbine treatment is feasible in elderly patients, and has a better response rate and longer median time to disease progression. However, both statistically significantly higher toxicity and no survival advantage for the combination treatment was observed.

Background/Purpose: This retrospective study was conducted to evaluate the drug resistance patterns of Mycobacterium tuberculosis in a medical center in northern Taiwan between 2003 and 2004 in comparison to those reported in 1990-1992. Methods: A total of 611 non-duplicate M. tuberculosis isolates from culture-proven tuberculosis (TB) cases were tested for drug susceptibility against five first-line anti-TB drugs in a clinical mycobacterial laboratory using the agar proportional method for isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and streptomycin (SM). The Wayne assay, which measures the activity of pyrazinamide (PZA), was used for PZA susceptibility testing. Results: Of 611 patients, including 510 males and 101 females, 70.2% of patients were older than 65 years. A total of 339 isolates (55.5%) were resistant to one or more drugs. Isolates from patients aged ＜25 years showed a significantly higher drug resistance rate (79.2%) compared with other age groups (p=0.0312). Single-drug resistance was observed in 97 (15.9%) of all isolates. Monoresistance to PZA (8.0%) was most frequent, followed by INH (5.1%), RIF (0.5%), EMB (1.6%), and SM (0.7%). Among the polydrug resistant isolates (PDR-TB), resistance rates were 35.5% for INH and 27.0% for RIF. One hundred and fifty-nine isolates (26.0%) were resistant to both INH and RIF (multidrug-resistant [MDR] TB); 94.6% of RIF-resistant isolates were also resistant to INH. The overall drug resistance rates and percentages of PDR-TB and MDR-TB increased over the 12-year study period (p＜0.001). Based on medical records, primary cases were identified in 486 (84.7%) out of 574 patients, and resistance to any drug was identified in 268 (55.1%) patients, of which 130 (26.7%) were MDR-TB. Among the 88 with recurrent TB, 54 (61.4%) were resistant to at least one drug, and MDR-TB was identified in 29 (33.0%) patients. A history of previous anti-TB therapy was a significant factor for overall drug resistance, PZA monoresistance, PDR-TB, and MDR-TB (p＜0.001). Conclusion: The emergence of M. tuberculosis isolates resistant to anti-TB agents in this hospital, and in particular among young patients, is alarming. Strict measures to control and prevent drug-resistant TB are urgently needed.

Though the imaging-based response (IBR) is the most frequently used index of the therapeutic effect in cancer patients, an index based on serum tumor markers might prove to be useful, especially in patients without measurable tumors.Paired pre- and post-treatment serum tumor markers (CEA, CA-125, and CA-199) were measured in 89 of 100 registered non-small cell lung cancer (NSCLC) patients who received gefitinib. Correlation and agreement analyses between the IBR at the 8th week and the tumor marker response (TMR) at the 4th or the 8th week were performed in patients with measurable lesions (n=68). Analysis of survival in relation to TMR was performed in all patients and in patients with no measurable lesions (n=21).IBR was closely correlated with individual tumor marker responses and the response of all 3 markers combined at 4 weeks (P values ranged from0.001 to 0.002). The agreements were also significant (P values ranged from 0.001 to 0.004). In the whole group, 4-week TMR was predictive for progression-free survival (P values ranged from0.0001 to 0.0086). In patients without measurable lesions, differences in progression-free survival and overall survival were closely correlated with the 4-week CA-125 response, CA-199 response, and TMR(overall) (P values ranged from 0.0002 to 0.0399). However, the correlation between the 8-week TMR and either IBR or survival was not significant.In gefitinib-treated NSCLC patients, correlation was good between 4-week TMR and IBR. Four-week TMR was predictive for survival. TMR may serve as a tool for assessing the gefitinib response in patients without measurable lesions.

Summary Background Intravenous vinorelbine plus cisplatin is widely prescribed for the treatment of NSCLC. The objective of this phase II study was to define the efficacy of an oral form of vinorelbine combined with cisplatin for first line treatment of advanced/metastatic NSCLC. Patients and methods From September 2002 to December 2003, 46 chemotherapy-naive patients received 80mg/m 2 of cisplatin on day 1 and oral vinorelbine at 60mg/m 2 on days 1 and 8, every 3 weeks. Results After an independent panel review, the response rate was 37.5 % [95% confidence interval (CI): 22.7–54.2%] in the evaluable population and 32.6% [95% CI: 19.5–48] in the intent-to-treat population. Median progression-free survival was 5.6 months and overall survival was 11.2 months. Grades 3 and 4 neutropenia was observed in 58.7% of patients, with febrile neutropenia and neutropenic infection in 4.3 and 8.7% of patients, respectively. The main non-haematological toxicities were hypotension, fatigue (8.7% for each) and gastrointestinal disorders with rare grades 3 and 4. Conclusions These results suggest that the combination of cisplatin at 80mg/m 2 on day 1 with oral vinorelbine at 60mg/m 2 on days 1 and 8, every 3 weeks, is an active regimen, associated with acceptable toxicity. Oral vinorelbine is therefore a good alternative to the i.v. formulation.

An 89-year-old man was admitted to the hospital due to intermittent anterior chest wall pain for > 1 month. A chest radiograph obtained on November 9, 2004, demonstrated a mass with an irregular border, inside a thin-walled cavity, located in the superior segment of the left lower lobe. A chest CT scan revealed an irregular thin-walled cavity, 5.9 × 5.4 × 4 cm in size, with an air-crescent sign in the superior segment of the left lower lobe, and an intracavitary fungus ball-like mass. A bronchoscopic examination was performed, revealing only external compression of the left lower lobe bronchial lumen. Cultures from both the brushing cytology and brushing fungus specimens were negative. Since the patient was a heavy smoker and the chest radiograph obtained 23 months before had revealed no active pulmonary lesion, neoplastic growth was still highly suspected. Thus, an 18 F-fluoro-2-deoxyglucose positron emission tomography study was performed on November 25, and a mass with a slightly increased standard uptake value (3.17; cutoff value, 2.5) was found. He received a left lower lobe lobectomy on December 23, and a tumor with many septum-like structures connecting the surrounding pulmonary parenchymal tissue was found in the superior segment of the left lower lobe. The final pathologic diagnosis was adenocarcinoma of the lung (pT2N0M0). Thus, even though the chest radiograph and chest CT scan showed a typical air-crescent sign ( ie , mass inside a cavity) favoring a mycetoma, the physician should still keep in mind that lung cancer may also unusually present in this way.

Background We used B16-F10 (B16) melanoma tumor cells and syngeneic C57BL/6 (B6) mice as a study model for pulmonary metastases, to better understand whether or not there exist differences in tumorigenicity and in the effectiveness of immunotherapy as a function of host age (1-, 3-, 12- and 24-month-old). Methods Intravenous injection of B16 melanoma cells were administered to B6 mice of different ages with/without interleukin (IL)-2 and IL-12 daily treatment. Tumor growth, splenocyte function, serum cytokines (IL-10, interferon-γ, vascular endothelial growth factor) and survival were compared. Results The study showed that, without IL-2 and IL-12 treatment, middle-aged mice suffering from pulmonary metas-tases had fewer pulmonary metastases and better survival than younger mice suffering from pulmonary metastases. Three days' IL-2 plus IL-12 treatment could not prolong mice survival, but prolonged treatment significantly improved the survival of both the younger and older tumor-bearing mice, especially the older mice, despite the fact that the younger mice had a better serum cytokine and splenocyte cellular immune response to cytokine treatment. Conclusion The young B6 mice that suffered from B16 pulmonary metastases had a poorer prognosis than the middle-aged mice. Short-term IL-2 plus IL-12 treatment is ineffective in prolonging survival, and a longer duration of treatment is needed. This kind of immunotherapy was effective in both the young and middle-aged mice, but it was more effective in the middle-aged mice.

BACKGROUND The use of liquid tissue, such as circulating cells, to predict treatment response is attracting more attention. OBJECTIVE The aim of this study was to evaluate association between circulating markers and treatment response. METHODS One hundred and twelve advanced pulmonary adenocarcinoma patients who were going to receive epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were included. Tumor tissue and plasma specimens were collected before treatment and analyzed for EGFR mutation and plasma IL-6 and IL-8. Pre-treatment peripheral blood CD146+/CD3- cells (as circulating endothelial cells, CECs), CD34+/CD45- cells (as endothelial progenitor cells, EPCs), and CD133+ cells (as cancer stem cells, CSCs) were measured with flow cytometry. RESULTS The progression-free survival (PFS) was significantly longer in patients with low CEC, low EPC, and low CSC counts than in those with high cell counts (p < 0.001, 0.041, and 0.001, respectively). Multivariate analysis showed that mutant plasma EGFR (pEGFR) was a poor prognostic factor in EGFR-mutated patients (p = 0.048), and there was a tendency for EGFR mutation-negative patients with high IL-6 level to have worse overall survival (p = 0.051). CONCLUSIONS CECs, EPCs, CSCs, and mutant pEGFR are useful predictive biomarkers of EGFR-TKI treatment efficacy. IL-6 may predict prognosis in advanced lung cancer.

Background. Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown. Materials and Methods. We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected. Results. In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were ≥70 years old (elderly group) and 170 were Conclusion. Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients. Implications for Practice: The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR-TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy.

Summary Purpose This phase II single arm, open label study was designed to evaluate the efficacy and toxicity of oral gefitinib (250 mg) daily in previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Methods Eligible patients had stage IIIB or IV NSCLC with adequate organ functions, and were chemonaive. All eligible patients were treated with oral administration of 250 mg of gefitinib until intolerable toxicity, disease progression or death occurred. Responses were assessed after every 8 weeks of therapy. Results For a total of 53 patients, the objective response rate (ORR) was 32.1% and overall disease control rate (DCR) was 52.8%. Median overall and progression-free survivals (PFS) were 9.4 (95% CI, 8.8–13.3) and 3.2 months (95% CI, 1.1–5.2) months, and 1-year survival rate was 41.5%. Patients with adenocarcinoma (n = 35) had a higher response rate. Adenocarcinoma, female gender (n = 24), and response to gefitinib were predictive factors for better survival. The most commonly seen adverse events (AEs) were skin toxicity (54.7%), diarrhea (43.4%) and nail change (16.9%). Most AEs were mild to moderate and considered manageable. Drug-related interstitial pneumonia was clinically diagnosed in four cases (7.5%). Conclusions Oral gefitinib, as compared to conventional chemotherapy, has comparable effect but less toxicity as a first-line treatment in Chinese patients who have advanced NSCLC, especially in those with adenocarcinoma histology. A further phase III prospective study comparing gefitinib to standard chemotherapy to define the efficacy of gefitinib is appropriate in advanced NSCLC patients.

Introduction The IRESSA Survival Evaluation in Lung Cancer (ISEL) phase III study compared the efficacy of gefitinib (IRESSA) versus placebo in patients with refractory advanced non-small cell lung cancer (NSCLC). Although a statistically significant difference in survival was not seen between gefitinib and placebo in the overall ISEL population, preplanned subset analyses demonstrated a significant survival benefit in patients who had never smoked and in patients of Asian origin. Methods In ISEL, 1692 patients who were refractory to or intolerant of their latest chemotherapy were randomized to receive either gefitinib (250 mg/day) or placebo, plus best supportive care. Preplanned subgroup analyses included an assessment of patients who were of Asian origin (n = 342). Results Two hundred thirty-five patients of Asian origin received gefitinib, and 107 received placebo. In these patients, treatment with gefitinib significantly improved survival compared with placebo (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.48, 0.91; p = 0.010; median survival, 9.5 versus 5.5 months). Patients of Asian origin also experienced statistically significant improvements in time to treatment failure with gefitinib compared with placebo (HR, 0.69; 95% CI, 0.52, 0.91; p = 0.0084; 4.4 versus 2.2 months), and objective response rates were higher with gefitinib than with placebo (12 versus 2%). Gefitinib was generally well tolerated in patients of Asian origin, with rash and diarrhea being the most common adverse events. No unexpected adverse events were observed. Conclusions Treatment with gefitinib was associated with a significant improvement in survival in a subgroup of patients of Asian origin with previously treated refractory advanced NSCLC.

Objective and background: The addition of an alternative class of long-acting bronchodilator is recommended for COPD patients who do not respond satisfactorily to monotherapy. The aim of this study was to investigate the additive benefit of tiotropium in severe COPD and to establish whether the improvement in lung function in these patients can be predicted from their acute bronchodilator response to ipratropium or salbutamol. Methodology: Forty-six patients with severe COPD treated with inhaled long-acting β2 agonists and corticosteroids (LABA/CS) were enrolled. Their prebronchodilator FEV1 was less than 50% of the predicted value. Tiotropium (18 µg, once daily) was added via a dry-powder inhaler device. After a month of treatment, tiotropium was stopped but their previous medication was continued. Patients were reassessed a month later. Acute bronchodilator response to ipratropium and salbutamol was assessed prior to tiotropium treatment. Pulmonary function and health status were evaluated. Results: Adding tiotropium significantly improved FVC, FEV1 and inspiratory capacity (IC). The increase in FVC was significantly associated with an increase in IC (r = 0.36, P = 0.019) and a decrease in residual volume (r =−0.56, P

BackgroundGender, smoking history, adenocarcinoma histology, performance status, and East Asian ethnicity were predictive factors of gefitinib response in previous analysis. However, these factors tend to be correlated with each other; it is not clear whether gender, smoking history, and adenocarcinoma histology were all independent predictors for response in East Asian populations.MethodsTumor response, survival and predictive factors of gefitinib response of advanced non-small cell lung cancer patients treated between May of 2002 and November of 2004 were collected retrospectively from three medical centers in Taiwan. Univariate and multivariate logistic regression models were used to test potential predictive factors associated with response to gefitinib. Overall survivals between groups with different predictive factors were compared by log-rank tests. Multivariate analyses were performed to identify factors that independently predict for survival.ResultsA total of 428 patients were analyzed. The median follow-up duration for living patients was 19.5 months (range, 10.2–39.9). Objective tumor response was observed in 114 patients (26.6%, 95% confidence interval [CI]: 22.4%–30.8%) and disease stabilization in 129 patients (30.2%). Response rate was statistically significant higher in adenocarcinoma, good performance status, and chemonaive patients in multivariate analysis. The median survival was 7.4 months (95% CI: 5.8–9.0) and 1-year survival was 34.3% (95% CI: 29.0%–38.0%). Significant independent predictive factors associated with longer survival in multivariate analysis were good performance status (p < 0.001) and responsiveness to gefitinib (p < 0.001). In 286 chemotherapy-treated patients, the response rate was 22.7%. Median and 1-year survival was 7.9 months and 36.7%, respectively. Good performance status was predictive of tumor response (p < 0.001) and better survival (p < 0.001) in multivariate analysis. Response to gefitinib was predictive of better survival (p < 0.001).ConclusionsGender and smoking status were not, but good performance status (PS), no previous chemotherapy, and adenocarcinoma histology were independent predictive factors in multivariate analysis for gefitinib response in Taiwanese advanced non-small cell lung cancer population. In patients previously treated with chemotherapy, only good PS was an independent predictor for tumor response in multivariate analysis.

Our aim was to determine the appropriate salvage regimen for Chinese non-small cell lung cancer (NSCLC) patients who failed previous chemotherapy. We retrospectively analyzed data from our seven clinical trials, including single-agent gemcitabine, gefitinib, docetaxel with a different schedule, vinorelbine plus cisplatin, vinorelbine plus gemcitabine, docetaxel plus gemcitabine, and docetaxel plus ifosfamide, with a total of 342 cases (including 314 patients, of which 28 entered two different trials due to different salvage line settings), and compared these data with those of other studies, addressing the efficacy and toxicity of salvage therapy in patients who failed previous chemotherapy to analyze choosing of an appropriate salvage regimen. Of the 342 cases receiving salvage treatment, 71.1% were in second-line treatment, and 28.9% in third-line or later treatment. The response rate to our salvage therapy ranged widely, from 6.1% to 36.1%. Median survival was between 5.7 and 8.4 months when different salvage chemotherapy regimens were used, whereas it was 9.3 months in those who received gefitinib treatment. Similarly, 1-year survival ranged between 19.7% and 40% in a chemotherapy setting, and 40.8% for gefitinib treatment. Those who received gefitinib had better toxicity profiles than those who received other regimens. Febrile neutropenia occurred in 19 patients who received a chemotherapy agent (6.2%), and four patients died despite granulocyte colony-stimulating factor and antibiotic treatment. Grade 3 or 4 interstitial pneumonitis occurred in 14 of 247 patients (5.7%) who received docetaxel with/without another agent, and 10 patients died. Grade 3 interstitial pneumonitis occurred in one patient who received gefitinib treatment and recovered. In conclusion, both chemotherapeutic agents, such as docetaxel alone or gemcitabine plus vinorelbine, and gefitinib, are probably appropriate salvage regimens for Chinese NSCLC patients who have failed previous chemotherapy. However, gefitinib has a better safety profile and probably better survival than the chemotherapeutic agents and would be an appropriate alternative choice for salvage chemotherapy, even in a second-line setting for Chinese patients.

Background/PurposeTo compare the efficacy and safety of tiotropium and ipratropium in patients with chronic obstructive pulmonary disease (COPD) in Taiwan.MethodsThis double-blind, randomized, placebo-controlled, parallel group study was conducted at six hospitals in Taiwan. COPD patients aged ≥ 40 years, with a forced expiratory volume in 1 second (FEV1) ≤65% of predicted and FEV1/forced vital capacity (FVC) ≤ 70% were enrolled. After a 2-week screening/baseline period, 132 patients were randomized to receive 4 weeks of treatment with either tiotropium 18 μg once daily from a dry powder inhaler (HandiHaler(r)) or two puffs of ipratropium 20 μg four times daily from a metered dose inhaler. The primary outcome was the change in trough FEV1 from baseline to week 4. The secondary outcome measures were trough FVC response, FEV1 and FVC responses at 2 hours postinhalation.ResultsAfter 4 weeks, trough FEV1 had increased by 61.7 + 25.3 mL for tiotropium but decreased by 16.4 + 27.9 mL for ipratropium. The difference between groups was significant (p

Background For orientals, titrating doses of docetaxel (60-66 mg/m(2)) have shown equal effectiveness and fewer side effects as a second-line chemotherapy for patients with advanced non-small cell lung cancer (NSCLC). Under such doses, there were no comparative data between classic tri-weekly and Days 1 and 8 weekly schedules. Methods This Phase II randomized prospective study was designed to compare the toxicity profile, efficacy and quality-of-life (QOL) between these two schedules of docetaxel in the treatment of previously treated patients with advanced NSCLC. Fifty patients were randomized to docetaxel arm A (66 mg/m(2) Day 1) and B (33 mg/m(2) Days 1 and 8) given every 3 weeks. Results The overall response rates (ORRs) were 12 and 24% in arm A and B, respectively (P = 0.46), and disease control rates were 52 and 48%. The median time-to-progression (TTP) was 11.3 and 12.7 weeks and median survivals were 33.4 and 27.6 weeks, respectively. Both arms have same 1 year (36%) and 2 year survivals (12%). Arm A had significantly higher neutropenia but less compromised QOL. In this study, the response of second-line chemotherapy was significantly better in the group that was response to front-line chemotherapy (P = 0.032). Conclusions While Days 1 and 8 weekly docetaxel schedules show higher ORR and less hematological toxicity, there is no advantage to tri-week schedule in terms of TTP and survival, but more compromised QOL.

Study objective To determine the appropriate chemotherapy regimen for inoperable, chemotherapy-nai¨ve non-small cell lung cancer (NSCLC) in elderly patients. Setting National teaching hospital in Taiwan. Design We retrospectively analyzed data from our clinical trials for a total of 270 patients and compared them with the data from other studies, addressing the elderly in particular or providing subgroup information on age, to analyze the feasibility of current chemotherapy options for elderly patients and possible alternative approaches. Results The response rates and median survival times of fit elderly patients with NSCLC who were receiving appropriate new anticancer drugs for chemotherapy, including single-agent or combination treatment, were no worse than those of younger patients, and the response rates may have been even higher in the elderly patients, while survival time was slightly poorer in this group. The risk of adverse side effects, such as myelosuppression and peripheral neuropathy, may be higher in elderly patients, who also visit the hospital more frequently. Some items on the lung cancer symptom scale for elderly patients were rated as being slightly worse than those for younger patients after chemotherapy. Conclusion Advanced age alone should not preclude chemotherapy. New single-agent drugs, and non-platinum-based or platinum-based doublets, can all be considered as appropriate treatment for selected fit elderly patients with advanced NSCLC.

Purpose: Mutations in epidermal growth factor receptor (EGFR) can be used to predict the tumor response of patients receiving gefitinib for non–small cell lung cancer (NSCLC). We investigated the association between mutations in EGFR tyrosine kinase domain and tumor response and survival in gefitinib-treated NSCLC patients. Experimental Design: EGFR mutations in exons 18 to 21 were analyzed by DNA sequencing of paraffin-embedded tumor tissues from gefitinib-treated NSCLC patients. The results were correlated with clinical variables. Results: EGFR mutations were found in 61.1% (33 of 54) of cases; response rate and disease control rate were 56.8% and 68.5%, respectively. There was no significant difference in mutation rates between adenocarcinoma (29 of 43) and nonadenocarcinoma (4 of 11; P = 0.085). However, all four nonadenocarcinomas with EGFR mutations had no response to gefitinib. Presence of EGFR mutations was the only independent predictor for disease control (P = 0.003) and tumor response (P = 0.017) in multivariate analysis; positive predictive values were 87.9% and 70.8% and negative predictive values were 61.9% and 69.2%, respectively. In comparison with patients whose tumor was negative for EGFR mutations, patients with EGFR mutations had better progression-free survival (median, 7.6 versus 1.7 months; P = 0.011) and overall survival (median, 14.7 versus 4.7 months; P = 0.046). Conclusions: Mutations in EGFR tyrosine kinase correlate with treatment response and survival in gefitinib-treated NSCLC patients and can be used as a predictive and prognostic factor. Thus, analysis of EGFR tyrosine kinase mutations in lung adenocarcinoma is of clinical significance, as it can permit the customization of treatment with EGFR tyrosine kinase inhibitors.

Background: The incidence of lung cancer (LC) is reported to be higher in patients with rheumatoid arthritis (RA). The present study investigated whether or not RA altered the clinical manifestation of LC. Methods: In this retrospective, cohort study, a total of 23 patients with both RA and LC (RA + LC group), and 6,570 patients with primary LC alone (LCA group), were identified from records at Taipei Veterans General Hospital between 1993 and 2002. Data about clinical characteristics, smoking habit, tumor location, LC histology, staging, and survival, were compared between the 2 groups. Results: There was no significant difference in mean age at LC diagnosis between the RA + LC and LCA groups (70.2 vs 67.6 years; p = 0.154). Adenocarcinoma was the major histologic type in both groups, especially among women. There was no significant difference in histology, location, or staging of LC between the RA + LC and LCA groups. In the RA + LC group, all patients had RA before LC was diagnosed; pulmonary fibrosis was noted in 3 patients, 1 of whom had secondary Sjogren’s syndrome. Median survival in the LCA group was not significantly different from that in the RA + LC group (10 [95% confidence interval, CI, 9.6, 10.4] vs 11 [95% CI, 3.7, 18.3] months; p = 0.69); the relative risk of LCA compared with RA + LC for survival was 0.938 (95% CI, 0.555, 1.585). The incidence of LC in RA patients in our hospital was 1.32% (23 of 1,740 patients). Conclusion: RA has no influence on LC stage and does not shorten the survival of LC patients. [J Chin Med Assoc 2005;68(5):216‐220]

Background In a phase II study, responses and toxicity to single-agent gemcitabine chemotherapy were evaluated in patients with non-small-cell lung cancer (NSCLC) who had failed previous cisplatin-based chemotherapy. Methods Twenty patients were enrolled from December 2001 to December 2003: 17 of them had received first-line cisplatin-based regimens and second-line docetaxel treatment; and 3 had previously received cisplatin plus paclitaxel. Study treatment comprised an intravenous infusion of gemcitabine 1,200 mg/m 2 on days 1, 8, and 15 of each 4-week cycle. Results Fifty-seven cycles of treatment were given (mean, 2.9 cycles per patient). All patients were evaluable for toxicity profile, and 16 were evaluable for response rate. The principal toxicity was myelosuppression: grade 3 neutropenia occurred in 2 patients (10%), thrombocytopenia in 3 (15%), and anemia in 1 (5%). Other toxicities were few and mild in severity. After 2 cycles of treatment, 2 of 16 patients (12.5%) had a partial response. The median time to disease progression was 2.1 months, and median survival time was 7.5 months. The 1-year survival rate was 36%. Conclusion Salvage, single-agent chemotherapy with gemcitabine has modest activity, is well tolerated, and yields good survival in NSCLC patients who have failed previous chemotherapy. Such single-agent therapy may therefore be suggested for use in patients with good performance status who ask for further chemotherapy, when disease progresses after cisplatin-based therapy, but especially after second-line docetaxel therapy.

Gefitinib, an orally active, selective inhibitor of epidermal growth factor-receptor tyrosine kinase, is an effective treatment for patients with advanced non-small-cell lung cancer (NSCLC). Most drug-related adverse events are mild to moderate; however, some patients may develop acute interstitial pneumonia that is sometimes fatal. In a prospective study of gefitinib in 76 patients with advanced NSCLC, 69 patients were evaluable for toxicity, and 4 cases (5.8%) of gefitinib-related interstitial pneumonia were diagnosed: 1 occurred in the second week; 2 in the second month; and 1 during the fourth month of treatment. When interstitial pneumonia occurred, the patients had stable disease (n = 2), a partial response (n = 1), or progressive disease (n = 1). All 4 patients recovered when gefitinib treatment was stopped and glucocorticosteroid therapy was started; no deaths related to gefitinib therapy were noted in this series. While treating NSCLC patients with gefitinib, it is important to carefully evaluate any new-onset respiratory symptoms and promptly arrange radiographic examinations, and to stop gefitinib treatment and begin glucocorticosteroid therapy whenever pulmonary toxicity is highly suspected.

Phase II studies have suggested that vinorelbine (V) plus gemcitabine (G) treatment has a similar response rate and better toxicity profile than cisplatin-based combination chemotherapy in non-small-cell lung cancer (NSCLC). Our aim was to evaluate whether or not the addition of cisplatin (P) to a VG regimen increases the efficacy or toxicities in chemo-naive inoperable NSCLC patients. From April 2002 to October 2003, 86 patients were enrolled. The treatment dose was V 20 mg/m2 plus G 800 mg/m2 intravenous infusion (i.v.) on days 1, 8 and 15, with/without P 60 mg/m2 i.v. on day 15, every 4 weeks. The efficacy and toxicity of the treatment were recorded. In all, 125 cycles of VG and 178 cycles of VGP were given to the patients in the VG and VGP arms, respectively (P = 0.001). The median cycle of treatment was three in the VG arm and five in the VGP arm. There were 10 partial responses (overall 23.3%) in the VG arm and 1 complete response and 19 partial responses (overall 46.5%) in the VGP arm (P = 0.022). Neutropenia, nausea, vomiting, and peripheral neuropathy were more common in the VGP arm (P = 0.023, 0.002, 0.025, 0.001, respectively). The Lung Cancer Symptom Scale showed no difference between the VG and VGP arms after two cycles of treatment or when the patient went off study. We concluded that the addition of P to VG treatment did increase both the tumor response rate and the toxicities. However, the toxicities were tolerable.

Study objectives: The management of stable patients with COPD depends on the severity of symptoms and airflow limitation. Regarding inflammation, corticosteroids are the only medications that are recommended for use, and only under restricted circumstances. Corticosteroids tend to undertreat or overtreat patients with COPD when only clinical manifestations and the findings of simple spirometry are considered. Accordingly, our aim was to survey the characteristics of airway inflammation in stable COPD patients, and to assess the interrelations among inflammatory cells, inflammatory mediators, bronchodilator reversibility, and pulmonary function. Factors related to airway inflammation and bronchodilator reversibility may be important in the management of stable COPD patients. Methods: A total of 88 stable patients with smoking-related COPD were recruited into the study. All patients were steroid-free, and had been treated with theophylline, oral 2-agonist agents, anticholinergic agents, and possibly mucolytic agents. Bronchodilator tests and sputum induction were performed to evaluate bronchodilator reversibility, and numbers of inflammatory cells and mediators (eg, interleukin [IL]-8, eotaxin, and regulated on activation, normal T cells expressed and secreted [RANTES]). Results: Thirty-one of 48 patients (64.6%) who had bronchodilator reversibility, and 19 of 40 patients (47.5%) without bronchodilator reversibility had sputum eosinophilia (median, 8.0% and 7.0%, respectively). FEV1 showed a significant inverse correlation with the number of sputum neutrophils. The correlation coefficient for postbronchodilator FEV1 vs the percentage of neutrophils in patients with nonreversible COPD was higher than that in those with reversible COPD. The levels of IL-8 were closely associated with the percentage of neutrophils. The sputum concentrations of IL-8 and albumin were significantly higher in patients with nonreversible COPD than in those with reversible COPD. A significant inverse correlation was found between bronchodilator response (ie, FEV1 and FVC) and prebronchodilator FEV1. Conclusions: Eosinophilic inflammation may play a substantial role in COPD, while neutrophils and IL-8 may have a great influence on nonreversible obstructive airways. The assessment of airway inflammation and bronchodilator responses can help the selection of specific therapies and the prediction of clinical outcomes for COPD patients. (CHEST 2004; 126:375–381)

Our aim was to describe the impact of severe acute respiratory syndrome (SARS) on the status and chemotherapy of non-small-cell lung cancer (NSCLC) patients who had entered clinical trials, and to review how to differentiate the signs and symptoms of SARS from lung cancer and its treatment-related toxicities. A prospective case series involving 79 NSCLC patients who were enrolled in clinical trials undergoing chemotherapy at Taipei Veterans General Hospital, between April 1 and July 15, 2003, was studied. Whether or not there existed a delay, omission, or refusal of scheduled chemotherapy, was recorded. Whether or not our patients had been suspected of or treated as having SARS, was recorded. The patients filled out questionnaires regarding lung cancer treatment and the risk of getting SARS from the hospital. Among these patients, five were placed in an isolation unit to rule out SARS infection during this period of time, and no patient was documented to have suffered from a SARS infection after examinations. Of 373 scheduled chemotherapy injections in 79 patients, a delay in treatment occurred only 10 times. Three patients refused further chemotherapy because of a fear of getting SARS if they visited the hospital. Fifty-eight patients responded to our questionnaires. Thirty-seven patients (63.8%) were afraid of visiting hospital during this SARS infection period. Twenty-one patients (36.2%) felt that a SARS infection was more severe and fatal than their lung cancer. In conclusion, SARS is a new disease entity that is highly contagious. Its clinical manifestations overlap with the signs and symptoms of lung cancer. Thus, a clear differentiation between the two conditions is needed, especially for those patients who are under active anti-cancer treatment.

Study objective Evidence for the anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited. There are also no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids. This study was designed to assess the clinical efficacy and anti-inflammatory effects of leukotriene receptor antagonist plus low-dose inhaled corticosteroids compared to those of a high-dose inhaled corticosteroid in patients with mild-to-moderate asthma. Methods Forty-nine patients with newly diagnosed asthma were recruited. They were randomly assigned to groups that received, for a 6-week period, either (1) budesonide, 600 μg bid (1,200 μg/d) or (2) budesonide, 200 μg (400 μg/d), and zafirlukast, 20 mg bid. The variables of asthma control were recorded daily. Sputum induction and methacholine provocation tests were performed. Results The results indicated that the administration of a low-dose inhaled corticosteroid plus zafirlukast was as effective as that of a high-dose inhaled corticosteroid regarding clinical improvement and anti-inflammatory effects ( ie , eosinophil percentage, and eosinophilic cationic protein [ECP] and cysteinyl leukotriene C 4 levels in induced sputum). Nineteen (group 1, 8 patients; group 2, 11 patients) of 49 patients (38.8%) had returned to normal airway responsiveness after treatment. Among these patients, 16 patients (84.2%) had normal ECP levels and 10 patients (52.6%) had normal percentages of eosinophils. ECP level, but not the eosinophil percentage, was significantly associated with symptom scores. The peak expiratory flow rate (PEFR) showed a significant correlation with the provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 ) instead of with symptom scores. Conclusions The addition of a leukotriene modifier to treatment with low-dose inhaled corticosteroids is equivalent to treatment with high-dose inhaled corticosteroids in patients with newly diagnosed mild-to-moderate asthma. In addition to symptoms and PEFR, the monitoring of ECP and PC 20 may be of great value in achieving optimal control of asthma.

Phase II studies have suggested that weekly paclitaxel has a higher response rate and better toxicity profile than the conventional schedule of once every 3 or 4 weeks. Our aim was to evaluate the efficacy of weekly paclitaxel plus cisplatin (PC) vs vinorelbine plus cisplatin (VC) in chemonaïve non-small-cell lung cancer (NSCLC) patients. From October 2000 to May 2002, 140 patients were enrolled. The treatment dose was P 66 mg m(-2) intravenous infusion (i.v.) on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, or V 23 mg m(-2) i.v. on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, every 4 weeks. In all, 281 cycles of PC and 307 cycles of VC were given to the patients in the PC and VC arms, respectively. There were 26 partial responses and one complete response (overall 38.6%) in the PC arm, and no complete responses, but 27 partial responses (overall 38.6%) in the VC arm. Myelosuppression was more common in the VC arm (P0.001). Peripheral neuropathy and myalgia were significantly more common in the PC arm (P0.001). The median time to disease progression was 6 months in the PC arm and 8.4 months in the VC arm (P=0.0344). The median survival time was 11.7 months in the PC arm and 15.4 months in the VC arm (P=0.297). We concluded that weekly PC is not suggested for NSCLC patients due to the relatively shorter progression-free survival and more common nonhaematological toxicities. British Journal of Cancer (2004) 90, 359-365. doi:10.1038/sj.bjc.6601526 www.bjcancer.com

Study objectives To determine the different effects of interleukin (IL)-2, IL-4, IL-7, IL-10, IL-12, and/or T-cell receptor (TCR)-CD3 engagement in recovering the functions of cytotoxic T lymphocytes (CTL) from malignant effusion. Setting National teaching hospital. Materials and methods Effusion-associated lymphocytes (EAL) were isolated from 35 malignant pleural effusions. Interferon (IFN)-γ production, proliferative response, and cytolytic activity of the cultured EAL against autologous tumors and K-562 cells were measured. Results It was found that EAL had a significantly depressed function. Stimulation with two signals, including IL-2 plus IL-7, IL-2 plus IL-12, or IL-2 plus TCR-CD3 engagement, could fully restore the functions of EAL, including IFN-γ production, proliferative response, and a specific increase in cytolytic activity against autologous tumor cells. IL-4 and IL-10, whether or not in combination with IL-2, did not augment the function of EAL, and even depressed it in some cases. The lymphocyte-depletion test showed that most of the recovered functions were from CD8 + CTL. Conclusion The depressed cellular function of EAL could be reversed with double signal stimulation, including IL-2 plus IL-7, IL-2 plus IL-12, or IL-2 plus TCR-CD3 engagement. These recovered cellular functions were mainly from CD8 + CTL.

The incidence of multiple primary malignancies has increased in recent decades. The present study attempts to determine the clinical characteristics, the smoking factor, prognosis and temporal relationship of lung cancer to other cancers in patients with multiple primary malignancies. A total of 193 patients with multiple primary cancers involving lung cancer were found among 22,405 cancer cases diagnosed in Taipei Veterans General Hospital, between 1993 and 1997. Patients' clinical characteristics, smoking habit, tumor location, lung cancer histology, staging and survival were recorded and analyzed. The results showed that smoking is a significant risk factor for the development of multiple primary malignancies involving lung cancer (P

Fas ligand (FasL) plays an important role in the regulation of apoptosis. Soluble FasL (sFasL) is produced by a cleavage of FasL from the cell surface by metalloproteinase. Whether or not sFasL exists or is elevated in the pleural effusion of different etiologies is unknown. The present study is designed to determine pleural effusion and serum sFasL levels under different clinical conditions, and ascertain if there exists a significant difference in the levels found in different clinical conditions, and whether this difference can be used as a tool for differential diagnosis. Soluble FasL levels in the pleural effusion and serum of 103 patients, including 37 with malignant pleural effusion, 24 with uncomplicated parapneumonic effusion, 8 with bacterial empyema, 16 with tuberculous pleurisy, and 18 with transudate effusion (8 with congestive heart failure and 10 with viral liver cirrhosis), were analyzed with ELISA assays. Pleural effusion from patients with bacterial empyema (median 79.4 pg/ml) and TB pleurisy (median 31.9 pg/ml) contained significantly higher amounts of sFasL than the pleural effusion from all other conditions studied (p

The role of new cytotoxic agents like gemcitabine has not yet been proven in the neoadjuvant settings. We designed a phase II study to test the feasibility of using gemcitabine and cisplatin before local treatment for stage III non-small cell lung cancer patients. Patients received three cycles of induction chemotherapy of gemcitabine (1000 mg m−2, days 1, 8, 15) and cisplatin (90 mg m−2, day 15) every 4 weeks before evaluation for operability. Operable patients underwent radical resection. Inoperable patients and patients who had incomplete resection received concurrent chemoradiotherapy with daily low dose cisplatin. All patients who did not progress after local treatment received three more cycles of adjuvant chemotherapy of gemcitabine and cisplatin. Fifty-two patients received induction treatment. Two patients had complete response and 31 patients had partial response (response rate 63.5%) after induction chemotherapy. Thirty-six patients (69%) were operable. Eighteen patients (35%) had their tumours completely resected. Two patients had pathological complete response. Median overall survival was 19.1 months, projected 1-year survival was 66% and 2-year survival was 34%. Three cycles of gemcitabine and cisplatin is effective and can be used as induction treatment before surgery for locally advanced non-small cell lung cancer patients. British Journal of Cancer (2002) 86, 190–195. DOI: 10.1038/sj/bjc/6600044 www.bjcancer.com © 2002 The Cancer Research Campaign

Background In patients with non-small cell lung cancer (NSCLC), the development of liver metastasis (LM) is a poor prognostic factor. Whether systemic treatment combined with local treatment for LM has benefit for NSCLC patients with LM is unknown. Methods We retrospectively reviewed and analyzed the clinical data and tumor epidermal growth factor receptor ( EGFR ) mutation status of 673 pulmonary adenocarcinoma patients, including 85 patients who developed LM at any time point in the course of the disease. Radiofrequency ablation (RFA) with real-time ultrasonographic guidance was used for local treatment of LM in these patients, if appropriate. Results Patients with an EGFR mutation were more prone to having synchronous LM than patients with EGFR wild-type (50.0% vs. 23.5%, P =0.019). Fifty-six patients (65.9%) had ≦5 LM nodules. The median overall survival (OS) of patients with ≦5 LM nodules was 7.6 months compared with 2.9 months for those with multiple nodules ( P EGFR mutation, synchronous LM and LM numbers. The independent prognostic factors for patients with ≦5 LM nodules were performance status, EGFR mutation, LM concomitant with adrenal metastasis and having received RFA. Patients who received RFA treatment ( n =6) had longer OS after LM than those without RFA treatment ( n =42) (23.1 vs. 7.9 months, P =0.035). Conclusions We recommend that patients with a better performance status and ≦5 LM nodules be considered for systemic treatment combined with RFA when LM develops.

The present study was designed to ascertain whether or not the pleural effusion and serum cytokine levels (granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-10 [IL-10], and interferon-gamma [IFN gamma]) in lung cancer patients differ from tuberculous (TB) pleural effusion, in which a strong cellular immune reaction is found; and, whether cytokine levels are a prognostic factor in lung cancer patients with malignant effusion. A total of 202 lung cancer patients with malignant pleural effusion and 26 patients with TB pleural effusion were studied consecutively between 1995 and 1998. Serum and effusion cytokine levels were analyzed with ELISA assays. The results showed that pleural effusion GM-CSF and IL-10 levels were significantly higher than serum levels in both cancer and TB patients. Pleural effusion IFN gamma levels were significantly higher than serum levels in TB patients. IFN gamma levels in both pleural effusion and serum were significantly higher in TB patients than in those with cancer. No significant difference was found, between TB and cancer patients, in the serum or pleural effusion levels of either IL-10 or GM-CSF. The ratio of pleural effusion IFN gamma to serum IFN gamma, effusion IFN gamma to effusion IL-10, and effusion IL-10 to serum IL-10, were all significantly higher in TB than in cancer patients, suggesting a higher cellular activity and T-helper 1 (Th1) reaction in TB pleural effusion than in malignant effusions, which were predominantly Th2 type. Survival analysis showed no significant difference in lung cancer patients with different levels of these cytokines. It was concluded that lung cancer patients with malignant pleural effusion had poorer immune profiles than those with TB pleurisy, both locally and systemically; and the cytokine profiles were not prognostic factors for lung cancer patients with malignant pleural effusion.

The aim of the present study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine, ifosfamide and cisplatin (GIP), administered every 3 weeks, in patients with inoperable non-small cell lung cancer (NSCLC). From October 1998 to July 1999, 18 previously untreated stages IIIb (4) and IV (14) patients were enrolled into the study. Gemcitabine and ifosfamide (with mesna as uroprotection) was administered on days 1 and 6, at a dose of 1000 and 1500 mg/m2, respectively; and cisplatin was given on day 1 at a dose of 60 mg/m2, every 3 weeks. All 18 patients were evaluable for response and toxicity profiles. One patient achieved a complete response, and II patients achieved a partial response, with an overall response rate of 66.7% (95%, CI, 45-89%). The main toxicity was hematological, a NCI grade 3-4 neutropenia in 16 patients (88.9%) during the treatment course. Febrile neutropenia occurred in three patients (16.6%). Grade 3 anemia occurred in eight patients (44.41%) and grade 3-4 thrombocytopenia occurred in 11 patients (61.1%). Non-hematological toxicity was mild and tolerable. No toxic death occurred. The median survival was 12.7 months and 1 year survival was 58.4%. The GIP combination chemotherapy produced a high response rate in advanced NSCLC; however, there was a relatively high percentage of hematological toxicity that still could be tolerated. A randomized trial comparing GIP to a two-drug combination of gemcitabine and cisplatin is planned.